The nicotinic acetylcholine receptor (nAChR) is a pentameric protein that forms a ligand-gated cationic channel. Lindstrom. (1997) Mol Neurobiol 15:193-222; Sharma and Vijayaraghavan (2002) J Neurobiol 53:524-534. The nAChR was first described in neurons, but has recently been identified in many cell types including endothelial cells (EC) and vascular smooth muscle cells. Macklin et al. (1998) J Pharmacol Exp Ther. 287:435-439. Intriguingly, ECs also synthesize and store acetylcholine. Parnavelas et al. (1985) Nature 316:724-725. Recently, it was discovered that nAChR activation causes ECs to form capillary tubes in vitro, and promotes angiogenesis in vivo. Heeschen et al. (2001) Nat Med 7:833-839; and Heeschen et al. (2002) J. Clin. Invest. 110:527-536.
Activation of the EC nAChR stimulates pathological neovascularization. Nicotine accelerates tumor angiogenesis and tumor growth in a murine Lewis lung cancer model. Heeschen et al. (2001) supra. The acceleration of tumor growth by environmental tobacco smoke is also mediated by nAChR-induced angiogenesis. Zhu et al. (2003) Cancer Cell 4:191-196. Furthermore, nAChR activation by nicotine stimulates the neovascularization and progression of atherosclerotic plaque. Heeschen et al. (2001) supra. Physiological as well as pathological angiogenesis can be mediated by this receptor. Activation, of the nAChR in a murine model of diabetic ulceration enhances wound angiogenesis and healing. Jacobi et al. (2002) Am J Pathol. 161:97-104. To date, the mechanisms of nAChR-mediated angiogenesis and their relationship to established angiogenic growth factors, such as VEGF and bFGF, are unknown.
Angiogenesis and vasculogenesis are processes involved in the growth of blood vessels. Angiogenesis is the process by which new blood vessels are formed from extant capillaries, while vasculogenesis involves the growth of vessels deriving from endothelial progenitor cells. Angiogenesis and vasculogenesis, and the factors that regulate these processes, are important in embryonic development, inflammation, and wound healing, and also contribute to pathologic conditions such as tumor growth, diabetic retinopathy, rheumatoid arthritis, and chronic inflammatory diseases.
There is a need in the art for methods of modulating angiogenesis, and methods of identifying agents that modulate angiogenesis.